Abstract
There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d(-/-)) or type I NKT cells (Jα18(-/-)). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubulointerstitium, which is the primary area of injury. Sulfatide-induced activation of type II NKT cells protected kidneys from IRI, but inhibition of NKT cell recruitment enhanced injury. In co-culture experiments, sulfatide-induced activation of NKT cells from either mice or humans attenuated apoptosis of renal tubular cells after transient hypoxia via hypoxia-inducible factor (HIF)-1α and IL-10 pathways. Renal tissue of patients with acute tubular necrosis (ATN) frequently contained NKT cells, and the number of these cells tended to negatively correlate with ATN severity. In summary, sulfatide-reactive type II NKT cells are renoprotective in IRI, suggesting that pharmacologic modulation of NKT cells may protect against ischemic injury.